The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B1) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, Mz, may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetic moment Mt. A signal is emitted by the excited spins after the excitation signal B1 is terminated, this signal may be received and processed to form an image.
When utilizing these signals to produce images, magnetic field gradients (Gx, Gy and Gz) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received NMR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.
Perfusion as related to tissue refers to the exchange of oxygen, water and nutrients between blood and tissue. The measurement of tissue perfusion is important for the functional assessment of organ health. Perfusion weighted images (PWI) show the degree to which tissues are perfused by the change in their brightness as a bolus of contrast agent washes through the vasculature, and can be used to assess the health of brain tissues that have been damaged by a stroke. A number of methods have been used to produce perfusion images using magnetic resonance imaging techniques. One technique, as exemplified by U.S. Pat. No. 6,295,465, is to determine the wash-in or wash-out kinetics of contrast agents such as chelated gadolinium. From the acquired NMR data, images are produced which indicate cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) at each voxel. Each of these perfusion indication measurements provides information that is useful in diagnosing tissue health.
Bolus tracking cerebral perfusion has expansive use in the clinical setting for imaging a variety of diseases including cerebrovascular occlusive disease, stroke, central nervous system tumors, and Alzheimer's disease. Parametric images of cerebral perfusion are calculated by analyzing the tracer kinetics of a known contrast agent, whether it is radio-labeled water in positron emission tomography (PET), an iodinated contrast agent in computed tomography (CT), spin-labeled water in arterial spin labeling MRI, or a paramagnetic contrast agent in dynamic susceptibility contrast (DSC) MRI. While the standard for quantification of cerebral perfusion still remains radio-labeled PET imaging, the requirement of a cyclotron for production of the radio-labeled tracer limits the availability of the technique. CT has the potential to quantify perfusion; however, iodinated contrast agents and large doses of radiation are required in this imaging method. This is problematic for frequent follow-up scan session as well as the use of the method in certain patient populations, such as young children.
MR-based perfusion imaging methods produce parametric images that only convey information relating to relative, and not quantitative, cerebral blood flow (rCBF) and cerebral blood volume (rCBV). Current methods for creating quantitative measurements of perfusion from MR imaging data rely on assuming population averaged values of normal appearing white matter (WM) and by setting the CBF values in this tissue to a preset value. This method has a poor correlation to PET imaging standards. Instead, a method which determines the quantitative CBF and CBV (qCBF and qCBV, respectively) on a subject-by-subject basis would be preferred.
Ischemic stroke is the third leading cause of death and disability in the industrialized world. In the US alone, between 500,000 and 750,000 people are affected by stroke each year. In an ischemic stroke, blood flow to parts of the brain is reduced below the metabolic needs and neuronal cell death ensues. Intracranial atherosclerosis is considered the leading cause of stroke worldwide. Intracranial atherosclerosis is caused by the accumulation of cholesterol plaque in the wall of an artery, causing progressive narrowing (stenosis) or complete blockage. Early detection and treatment of an intracranial stenosis has the potential to prevent a stroke. There is high rate of stroke in cases of stenosis greater that 70% despite maximal medical therapy. Conversely, many patients develop adequate collateral circulation to compensate for even severe stenosis without the need for intervention.
There is currently no robust way to evaluate the degree to which individuals are able to compensate for the presence of an intracranial stenosis, an extra-cranial stenosis, trauma, vascular malformations, etc. Angioplasty and stenting of stenosis may help patients with insufficient collateral flow, but the procedure carries a significant risk indicating the need for a more definitive method of identifying patients who will benefit from it.
Therefore, an objective measurement of the adequacy of cerebral perfusion downstream to the lesion should be central to treatment decision making Studies of relative perfusion with a stress challenge (i.e. Acetezolemide) are well known but are subjective and limited by the high likelihood of contralateral disease.
The viability of the brain parenchyma depends on the ability of the blood supply to adequately perfuse the tissue. In an ischemic stroke, blood flow to parts of the brain is reduced below the metabolic needs and neuronal cell death ensues. Atherosclerosis caused by the accumulation of cholesterol plaque in the wall of an artery in the arteries of the neck and head, is considered the leading cause of stroke worldwide. There is a high rate of stroke in cases of progressive narrowing (stenosis) of the arteries of the head and neck greater that 70% despite maximal medical therapy. Conversely, many patients develop adequate collateral circulation to compensate for even severe stenosis or complete blockage (occlusion) without the need for intervention. In a setting of vascular disease the ability to compensate for vascular disease is reduced although symptoms of the decrease symptoms are not observable. In patients with cerebrovascular disease, a higher risk of stroke is associated with inability to regular cerebral blood flow quantified by Cerebro-vascular Reserve (CVR).
The progression of cerebrovascular disease can be characterized in terms of three stages of hemodynamic failure. The three stages reflect the ability of the arteries of the head to compensate to the presence of a flow limiting stenosis in the head/neck. In this model the severity of compromise, i.e. the stage is reflected in changes in the cerebral blood volume, cerebral blood flow and oxygen extraction of the affected brain. In patients in the final stages of hemodynamic failure (stage III), it is found that Oxygen Extraction Fraction (OEF) was increased by as much has 50% relative to Stage I or Stage II failure. The increases of OEF values were measured with positron emission tomography scans and were able to predict which patients were likely to have a stroke. In other words, determining the stage of hemodynamic failure will likely provide a tool by which more aggressive management of atherosclerosis can help prevent a stroke. Although very useful, the need for an on-site cyclotron for the production of the specific radioactive tracer has limited this approach to a handful of research hospitals.
There have been a number of imaging approached to quantify CVR with a ACZ challenge. Compute tomography (CT) perfusion using Xe has been studied for over 20 years in evaluating cerebral perfusion. Xe-CT requires the presence of an anesthetist due to the pharmacologic and side effects of Xe inhalation which include headache, vomiting, decrease respiratory rate and convulsion. Xe-CT is not currently approved for use by the US FDA.
A more recent approach to CT perfusion involves tracking a bolus of contrast agent as if flows through the head. CT perfusion exposed the patient to high doses of radiation and quantitative values have not been shown to be robust. In the prevention of stroke, where two scans and periodic follow up may be required, the cumulative radiation dose should be minimized.
A recognized reference standard for quantitative cerebral perfusion is positron emission tomography (PET). Unlike standard FDG-PET scans, PET perfusion and OEF measurements require an on-site cyclotron to produce the short half life (122.24 s) radioactive tracer. The need for the cyclotron has limited PET perfusion to use at a fewer than 10 research sites in the US.
While technically not an imaging modality, it is possible measure global (i.e. hemispheric) changes in CVR measures with ACZ via transcranial Doppler ultrasonography of the middle cerebral artery. It may be less sensitive to detect compromised CVR than direct measurement of cerebral perfusion by Xe/CT (useful but single hemisphere).
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.